The benzimidazole derivatives are polymeric benzimidazoles of the formula I: 
wherein R6=H or CH3, X=xe2x80x94OCOCH2COOxe2x80x94, 
or xe2x80x94CONHCH2NHCOxe2x80x94, R7=H, CH3, C2H5 or CONH2, Y=OH or NH2, E=xe2x80x94COOxe2x80x94, B is benzimidazole moiety of the formula IIA: 
wherein each of R1, R2, R3, R4, R5=H, C1-12 alkyl, C6-12 (un)substituted aryl, C1-8 alkoxy, C6-12 aryloxy, C1-5 alkoxy carbonyl, C6-12 aryloxy carbonyl, C1-5 alkoxy alkyl, C6-12 alkoxyaryl, C1-5 haloalkyl, C1-5 alkyl, C1-5 haloalkoxyl alkyl or C6-12 aryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic ring systems or enantiomers thereof.
This invention also relates to pharmaceutically acceptable acid addition salts of the acid stable antiulcer polymeric benzimidazoles, process for the preparation thereof and formulation comprising the same.
The compounds of the invention on oral administration inhibit exogenously or endogenously stimulated gastric acid secretion and thus may be used in the treatment/prevention of peptic ulcers, gastro intestinal inflammatory diseases like duodenal/gastric ulcer or gastritis or other gastro intestinal disorders.
Antiulcer benzimidazoles of the formula II: 
wherein each of R1, R2, R3, R4, R5 is as defined above, are known to be unstable at neutral or acidic pH of the gastric fluid and undergo decomposition in gastrointestinal fluid on oral administration resulting in loss of activity. Therefore, these compounds are not directly orally ingested. Instead, they are formulated for use by enteric coating or by N-substitution with non-polymeric substituents followed by enteric coating [U.S. Pat. Nos. 4,045,563, 5,039,806 and 5,948,773, PCT Publications Nos WO 95/32957, WO 94/27988 and WO 91/19711, EP Patents Nos 176308 and 0045200 and J. Med. Chem., 34,1049(1991) John Sih et al].
Enteric coated formulations in the form of tablet comprise an initial barrier coating on the active with polymers such as hydroxy propyl methyl cellulose, polyvinyl pyrrolidone or the like, followed by acid resistant coating with polymers such as cellulose acetate phthalate, hydroxy propyl methyl phthalate, polyvinyl acetate phthalate or copolymer of methacrylic acid and ethyl acrylate. The method of preparing enteric coated tablets involves provision of multiple coatings and numerous unit operations such as communition, blending, pelletisation, pan coating, drying, spray coating and/or fluid bed coating/drying because of which it is cumbersome, time consuming and expensive. Benzimidazole actives being sensitive to light, moisture and organic solvents such as dichloromethane acetone or isopropyl alcohol, there are chances of decomposition of the actives during pelletisation thereof. The biologically active compound from such enteric coated formulation is directly released in neutral pH in the intestinal fluid bypassing contact with acidic gastric fluid, where a good percentage of the active is decomposed due to its instability in neutral pH. Thus the bioavailabilty of benzimidazole actives from enteric coated formulations thereof is low. Anti-ulcer benzimidazoles are not known or reported to have been formulated into other oral dosage forms such as syrup or suspension.
Bioactives other than benzimidazoles covalently conjugated with synthetic polymers directly or through a reactive functional group are known and reported. For example, progesterone has been conjugated with aliphatic polyesters such as poly-(xcex5-Caprolactone), poly-[xcex5-(+,xe2x88x92)-Calactone], polypivlolactone and poly-(+,xe2x88x92)-dilactide through an ester linkage [(Biomed. Mater. Res, Pitt et al, 1979, 13, 497); (Polymer conjugates with Anticancer Activity, Advances in Polymer Science, D Putnam et al, 1995, Vol 122, page 55-123, Springer Verlag Berline)]. These polymer-conjugates are administered by subdermal route.
U.S. Pat. No 4,587,046 describes covalent conjugation of nearly occuring catecholamines and autocoid moieties with monodisperse amino acid polymers or peptides having an alkyl group through ester/amide linkages. These conjugates are administered parenterally.
U.S. Pat. No. 5,783,178 describes conjugation of actives like vinca alkaloids, mitomycins, bleomycins, fluconazole, amphotericin B, paclitaxel derivatives, cytokines, erythroprotein or polynucleotides with block copolymer of ethyleneoxy monomer or a mixture of ethyleneoxy and the xe2x80x94OCH(CH3)CH2xe2x80x94 monomers through bifunctional linking group. This system is mainly used as targeted drug delivery system.
U.S. Pat. No. 5,510,418 describes covalent conjugation of glycosaminoglycan with polyethylene glycol through an ether linkage and is useful for hard/soft tissue augmentation. These polymer-conjugates are to be administered by parenteral route.
Biphenylamine derivatives have been conjugated with polymethacrylic acid. Release of the biphenyl amine derivative from the conjugate was reported only after intraperitoneal injection.
U.S. Pat. No. 5,889,078 describes conjugates of biologically active compounds such as cytostatic fluoro uracil with homopolymer of acrylic acids through ester or amide linkages. These polymer conjugates are mainly used as drug delivery system by parenteral route wherein the polymeric backbone after release of the bioactives is difficult to be excreted from the biological system.
U.S. Pat. No. 5,037,883 describes conjugate of active such as anticancer daunomycin with copolymer of N-(2-hydroxypropyl) acrylamide, N-methacrylamide, N-methacrylic acid and/or N-methacryloylated amino acid through peptide group. These polymer-conjugates are administered by parenteral route.
U.S. Pat. No. 5,976,527 describes conjugates of proteins such as albumin, immunoglobulins, blood clotting factors and peptide hormones with polmethylmethacrylate or polymeth acrylamide comprising reactive oxirane groups, which after immobilisation are used for interaction with biological systems. These conjugate systems are mainly used for diagnostic purposes and as sorbents for pollutants.
Benzimidazole compounds substituted with polymer at the nitrogen thereof are not known or reported.
An object of the invention is to provide orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, having increased bioavailability.
Another object of the invention is to provide orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which are not enteric coated.
Another object of the invention is to provide orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which have activity comparable to unsubstituted benzimidazoles.
Another object of the invention is to provide orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof which are capable of being clinically used.
Another object of the invention is to provide a process for the preparation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof which results in products having increased bioavailabilty.
Another object of the invention is to provide a process for the preparation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which results in products that are not enteric coated and is therefore simple, less time consuming, less expensive, easy and convenient to carry out.
Another object of the invention is to provide a process for the preparation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which results in products having activity comparable to the unsubstituted benzimidazoles.
Another object of the invention is to provide a process for the preparation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which results in products capable of being used clinically.
Another object of the invention is to provide a formulation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, having increased bioavailability.
Another object of the invention is to provide a formulation of orally administrable acid stable anti-ulcer polymeric benzimidazoles and pharmaceutically acceptable salts thereof, which are not enteric coated.
Another object of the invention is to provide a formulation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which have activity comparable to the unsubstituted benzimidazoles.
Another object of the invention is to provide a formulation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which are capable of being used clinically.
According to the invention there is provided orally administrable acid stable anti-ulcer benzimidazole derivatives of the formula I: 
wherein R6=H or CH3, X=xe2x80x94OCOCH2COOxe2x80x94, 
or xe2x80x94CONHCH2NHCOxe2x80x94, R7=H, CH3, C2H5 or CONH2, Y=OH or NH2, E=xe2x80x94COOxe2x80x94, B is benzimidazole moiety of the formula IIA: 
wherein each of R1, R2, R3, R4, R5=H, C1-12 alkyl, C6-12 (un)substituted aryl, C1-8 alkoxy, C6-12 aryloxy, C1-5 alkoxy carbonyl, C6-12 aryloxy carbonyl, C1-5 alkoxy alkyl, C6-12 alkoxyaryl, C1-5 haloalkyl, C1-5 alkyl, C1-5 haloalkoxy alkyl or C6-12 aryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic ring systems or enantiomers thereof; and pharmaceutically acceptable acid addition salts thereof.
According to the invention there is also provided a process for the preparation of orally administrable acid stable anti-ulcer benzimidazole derivatives of the formula I: 
wherein R6=H or CH3, X=xe2x80x94OCOCH2COOxe2x80x94, 
or xe2x80x94CONHCH2NHCOxe2x80x94, R7=H, CH3, C2H5 or CONH2, Y=OH or NH2, E=xe2x80x94COOxe2x80x94, B is benzimidazole moiety of the formula IIA: 
wherein each of R1, R2, R3, R4, R5=H, C1-12 alkyl, C6-12 (un)substituted aryl, C1-8 alkoxy, C6-12 aryloxy, C1-5 alkoxy carbonyl, C6-12 aryloxy carbonyl, C1-5 alkoxy alkyl, C6-12 alkoxyaryl, C1-5 haloalkyl, C1-5 alkyl, C1-5 haloalkoxy alkyl or C6-12 aryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic ring systems or enantiomers thereof; and pharmaceutically acceptable acid addition salts thereof, the process comprising:
a) condensing a benzimidazole of the formula II: 
wherein each of R1, R2, R3, R4, R5 is as defined above, with a biocompatible partially orally biodegradable synthetic cross linked polymer of the formula III: 
wherein R6, R7, X and E each is as defined above and Yxe2x80x2=O or N, in aqueous medium at 5-80xc2x0 C. and pH 4-11 under inert atmosphere and stirring; the weight percentage of the benzimidazole with respect to the conjugate being 1-50;
b) cooling, isolating and drying the resulting polymeric benzimidazole at 25-45xc2x0 C.; and
c) if desired, converting the polymeric benzimidazole into pharmaceutically acceptable acid addition salts.
According to the invention, there is also provided a formulation of orally administrable acid stable anti-ulcer benzimidazole derivatives of the formula I: 
wherein R6=H or CH3, X=xe2x80x94OCOCH2COOxe2x80x94, 
or xe2x80x94CONHCH2NHCOxe2x80x94, R7=H, CH3, C2H5 or CONH2, Y=OH or NH2, E=xe2x80x94COOxe2x80x94, B is benzimidazole moiety of the formula IIA: 
wherein each of R1, R2, R3, R4, R5=H, C1-12 alkyl, C6-12 (un)substituted aryl, C1-8 alkoxy, C6-12 aryloxy, C1-5 alkoxy carbonyl, C6-12 aryloxy carbonyl, C1-5 alkoxy alkyl, C6-12 alkoxyaryl, C1-5 haloalkyl, C1-5 alkyl, C1-5 haloalkoxy alkyl or C6-12 aryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic ring systems or enantiomers thereof; and pharmaceutically acceptable acid addition salts thereof, in combination with pharmaceutically acceptable excipients.
The compounds of the formula II may be racemic or enantiomeric.
Preferably the compound of the formula II may be 5-methoxy-2[(4-methoxy-3,5-dimethyl-2-pyridinyl)sulfinyl]-1H-benzimidazole i.e. omeprazole, wherein R1=CH3, R2=OCH3, R3=CH3, R4=OCH3, R5=H; or 5-(difluoro methoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole ie pantoprazole, wherein R1=H, R2=OCH3, R3=OCH3, R4=OCHF2, R5=H; or 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole ie lansoprazole, wherein R1=H, R2=OCH2CF3, R3=CH3, R4=H, R5=H.
The polymers may be formed in known manner by polymerisation of monomers such as acrylic acid, substituted acrylic acids, acrylamide, substituted acrylamides, acrylonitrile, substituted acrylontriles, esters of acrylic or substituted acrylic acids, styrene, vinyl styrene, vinyl anhydride or derivatives thereof, preferably acrylic acid, methacrylic acid, acrylamide, methacrylaide, acrylonitrile, ethyl acrylate, methyl acrylate, butyl acrylate, hydroxyethylmethyl acrylate or 2-hexylethylmethacrylate.
Preferably Yxe2x80x2 in the polymer of the formula III is oxygen atom and Y in the polymeric benzimidazole of the formula 1 is hydroxyl group.
Pharmaceutically acceptable acid addition salts of the conjugate may be hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, perchlorate, formate, acetate, propionate, succinate, glycolate, lactate, tartarate, citrate, ascorbate, piruvate or alginate prepared in a known manner by treating the polymeric benzimidazole with acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid, perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, pyruvic acid, or alginic acid respectively.
The weight percentage of the benzimidazole of the formula II may be preferably 20% with respect to the conjugate.
The condensation pH may be preferably 6-11.
The temperature for condensation may be preferably 10-40xc2x0 C.
Isolation of the polymeric benzimidazole may be by filtration, decantation or centrifugation, preferably filtration.
The polymeric benzimidazole may be dried in a tray dryer or vacuum tray dryer, preferably tray dryer, preferably at 30-50xc2x0 C.
The excipients may be lactose, magnesium stearate, methyl cellulose, distilled water, microcrystalline cellulose, maltodextrin, glycerin, flavouring agents or other excipients known in the art.
The polymeric benzimidazoles of the invention are novel and are found to be acid stable due to the polymeric N-substitution. Therefore, they do not disintegrate in the gastrointestinal fluid and are suitable for oral administration without enteric coating. Since they do not disintegrate in the gastrointestinal fluid, their bioavailability is increased as compared to enteric coated benzimidazoles and their activities are comparable to those of unsubstituted benzimidazoles. Because the process for the preparation of the compounds of the invention eliminates enteric coating, it is simple, less time consuming, less expensive, easy and convenient to carry out. Upon oral administration, under the influence of enzymes/chemicals in the gastrointestinal fluid, the polymeric benzimidazole cleaves at the hydrolysable group (E) to release a N-substituted benzimidazole derivative (ie the benzimidazole along with a part of the polymer) having anti-ulcer activity. The remaining part of the polymer is inert, non-toxic and non-absorbable in the gastro intestinal fluid and is excreted from the body as such or as nonabsorbable metabolites thereof. Therefore the polymeric benzimidazole conjugates of the invention are safe for clinical use. The polymeric benzimidazoles of the invention may be formulated into tablets or capsules besides other oral dosage forms such as syrup or suspension.
The following experimental examples are illustrative of the invention but not limitative of the scope thereof.